Abstract：
BACKGROUND: Determination of a drug\'s potency in blocking the hERG channel is an established safety pharmacology study. Best practice guidelines have been published for reliable assessment of hERG potency. In addition, a set of plasma concentration and plasma protein binding fraction data were provided as denominators for margin calculations. The aims of the current analysis were five-fold: provide data allowing creation of consistent denominators for the hERG margin distributions of the key reference agents, explore the variation in hERG margins within and across laboratories, provide a hERG margin to 10 ms QTc prolongation based on several newer studies, provide information to use these analyses for reference purposes, and provide recommended hERG margin \'cut-off\' values.
METHODS: The analyses used 12 hERG IC50 \'best practice\' data sets (for the 3 reference agents). A group of 5 data sets came from a single laboratory. The other 7 data sets were collected by 6 different laboratories.
RESULTS: The denominator exposure distributions were consistent with the ICH E14/S7B Training Materials. The inter-occasion and inter-laboratory variability in hERG IC50 values were comparable. Inter-drug differences were most important in determining the pooled margin variability. The combined data provided a robust hERG margin reference based on best practice guidelines and consistent exposure denominators. The sensitivity of hERG margin thresholds were consistent with the sensitivity described over the course of the last two decades.
CONCLUSIONS: The current data provide further insight into the sensitivity of the 30-fold hERG margin \'cut-off\' used for two decades. Using similar hERG assessments and these analyses, a future researcher can use a hERG margin threshold to support a negative QTc integrated risk assessment.
METHODS: The analyses used 12 hERG IC50 \'best practice\' data sets (for the 3 reference agents). A group of 5 data sets came from a single laboratory. The other 7 data sets were collected by 6 different laboratories.
RESULTS: The denominator exposure distributions were consistent with the ICH E14/S7B Training Materials. The inter-occasion and inter-laboratory variability in hERG IC50 values were comparable. Inter-drug differences were most important in determining the pooled margin variability. The combined data provided a robust hERG margin reference based on best practice guidelines and consistent exposure denominators. The sensitivity of hERG margin thresholds were consistent with the sensitivity described over the course of the last two decades.
CONCLUSIONS: The current data provide further insight into the sensitivity of the 30-fold hERG margin \'cut-off\' used for two decades. Using similar hERG assessments and these analyses, a future researcher can use a hERG margin threshold to support a negative QTc integrated risk assessment.
摘要：
背景：确定药物阻断hERG通道的效力是一项既定的安全性药理学研究。已发布最佳实践指南以可靠地评估hERG效力。此外,我们提供了一组血浆浓度和血浆蛋白结合分数数据作为边际计算的分母.当前分析的目的是五倍：提供数据，允许为关键参考试剂的hERG边际分布创建一致的分母，探索实验室内部和跨实验室的hERG边距的变化，根据几项较新的研究，提供10msQTc延长的hERG裕度，提供信息以使用这些分析作为参考，并提供推荐的hERG边距“截止值”。
方法：分析使用12个hERGIC50“最佳实践”数据集（用于3种参考药物）。一组5个数据集来自一个实验室。其他7个数据集由6个不同的实验室收集。
结果：分母暴露分布与ICHE14/S7B培训材料一致。hERGIC50值的间期和实验室间变异性是相当的。药物间差异在确定合并边缘变异性方面最重要。合并后的数据基于最佳实践指南和一致的暴露分母提供了可靠的hERG余量参考。hERG边缘阈值的灵敏度与过去二十年中描述的灵敏度一致。
结论：当前数据提供了对使用了20年的30倍hERG边缘\'截止值\'的敏感性的进一步了解。使用类似的hERG评估和这些分析，未来的研究人员可以使用hERG裕度阈值来支持负面的QTc综合风险评估.
方法：分析使用12个hERGIC50“最佳实践”数据集（用于3种参考药物）。一组5个数据集来自一个实验室。其他7个数据集由6个不同的实验室收集。
结果：分母暴露分布与ICHE14/S7B培训材料一致。hERGIC50值的间期和实验室间变异性是相当的。药物间差异在确定合并边缘变异性方面最重要。合并后的数据基于最佳实践指南和一致的暴露分母提供了可靠的hERG余量参考。hERG边缘阈值的灵敏度与过去二十年中描述的灵敏度一致。
结论：当前数据提供了对使用了20年的30倍hERG边缘\'截止值\'的敏感性的进一步了解。使用类似的hERG评估和这些分析，未来的研究人员可以使用hERG裕度阈值来支持负面的QTc综合风险评估.
